The present invention relates generally to antibiotic mitosane compounds and to their use in the treatment of neoplastic disease states in animals.
The disclosures of my U.S. Pat. Nos. 4,268,676, 4,460,599 and 4,617,389; my pending application U.S. Ser. No. 629,814, filed July 11, 1984, now U.S. Pat. No. 4,885,304 which is a divisional application of U.S. Pat. Nos. 4,268,676 and 4,460,599; my co-pending continuation-in-part U.S. patent application Ser. No. 464,612 now abandoned, which was abandoned in favor of U.S. Ser. No. 757,194, filed on July 22, 1985 and my co-pending U.S. patent application Ser. No. 647,055, filed Sept. 4, 1984 now U.S. Pat. No. 4,888,341 are specifically incorporated herein by reference to the extent that they may provide essential and nonessential material relating to the present invention.
Briefly summarized, said U.S. Pat. Nos. 4,268,676, 4,460,599 and 4,617,389 set forth a statement of the background of the ongoing search in the art for new and useful compounds structurally related to the mitomycins, which not only possess antibiotic activity, but, in addition, possess the unexpected properties of low toxicity and significant antineoplastic activity in animals. More particularly, they disclose new compounds of the formula I, ##STR2##
wherein: Y is hydrogen or lower alkyl; and X is a thiazolamino radical, a furfurylamino radical or a radical of the formula, ##STR3## in which R, R.sup.1 and R.sup.2 are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R.sup.3 is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, thienyl, formamyl, tetrahydrofuryl and benzene sulfonamide.
Said U.S. patents also disclose novel methods for treatment of neoplastic disease states in animals, which methods comprise administering a therapeutically effective amount of a compound of the formula, Ia, ##STR4##
wherein Y is hydrogen or lower alkyl; and Z is a thiazolamino radical, a furfurylamino radical, a cyclopropylamino radical, a pyridylamino radical, or a radical of the formula, ##STR5## in which R.sup.4, R.sup.5, and R.sup.6 are the same or different and selected from the group consisting of hydrogen and lower alkyl, and R.sup.7 is selected from the group consisting of lower alkenyl, halo-lower alkenyl, lower alkynyl, lower alkoxycarbonyl, halo-lower alkyl, hydroxy-lower alkyl, pyridyl, thienyl, formamyl, tetrahydrofuryl, benzyl, and benzene sulfonamide.
Said U.S. Patents also disclose novel methods for treatment of neoplastic disease states in animals, which methods comprise administering an effective amount of the compound of the formula, IIa, ##STR6##
wherein: Y is hydrogen or lower alkyl; and Z is a lower alkoxy substituted quinolinylamino radical, a cyano substituted pyrazolylamino radical or a mono- or di-lower alkyl substituted thiazolamino radical, or
a nitrogen-containing heterocyclic radical, or
a cyano, phenyl, carboxamido or lower alkoxycarbonyl substituted 1-aziridinyl radical, or
a lower alkyl, formyl or acetylphenyl substituted 1-piperazinyl radical, or
an hydroxy or piperidyl substituted 1-piperidyl radical, or
a lower alkoxy, amino or halo substituted pyridylamino radical, or
a carboxamido, mercapto or methylenedioxy substituted anilino radical, or
a radical of the formula, ##STR7##
wherein R is hydrogen or lower alkyl and R" is a nitrogen-containing heterocyclic radical, or
a butyrolactonyl radical, or
an adamantyl radical, or
a mono-lower alkoxy substituted phenyl radical, or
a substituted lower alkyl radical selected from the group consisting of mercapto lower alkyl, carboxy lower alkyl, mono-k di- and tri-lower alkoxy lower alkyl, lower alkyl thio lower alkyl and lower alkoxycarbonyl substituted derivatives thereof, cyano lower alkyl, mono-, di- and tri-lower alkoxy phenyl lower alkyl, phenyl cyclo lower alkyl, 1-pyrrolidinyl lower alkyl, N-lower alkyl pyrrolidinyl lower alkyl, N-morpholinyl lower alkyl, and lower dialkylamino lower alkyl.
Continuation-in-part U.S. patent application Ser. No. 757,194 also discloses compounds for use in treatment of neoplastic disease states in animals of the formula, IIIa, ##STR8##
wherein: Y is hydrogen or lower alkyl; and Z is an hydroxy substituted 1-pyrrolidinyl radical, or a lower alkyl substituted piperidyl radical, or a 1-piperazinyl radical or an acetamino, acetyl, carbamido, cyano, carboxy lower alkylamino, di-lower alkoxy, nitro, sulfamyl, or lower alkyl substituted anilino radical, or a radical of the formula, ##STR9##
wherein R is hydrogen or lower alkyl and R.sup.1 is a nitrogen containing heterocyclic radical selected from the group consisting of amino substituted triazolyl, lower alkyl substituted isothiazolyl, benzothiazolyl, and nitro and halo substituted derivatives of benzothiazolyl, or
R.sup.1 is a substituted lower alkyl radical selected from the group consisting of amino lower alkyl, lower alkylamino lower alkyl, hydroxy lower alkylamino lower alkyl, hydroxy lower alkoxy lower alkyl, imidazolyl lower alkyl, nitro substituted imidazolyl lower alkyl, mono- and dihydroxy phenyl lower alkyl, nitro substituted pyridylamino lower alkyl, piperazinyl lower alkyl, and pyridyl ethyl.
Also of interest to the present application is Urakawa, C., et al., J. Antibiotics, 33: 804-809 (1980). which discloses the synthesis and biological evaluation of a series of 7-alkoxymitosanes including 7-ethoxy, 7-n-propoxy, 7-i-propoxy, 7-n-butoxy, 7-i-butoxy, 7-sec-butoxy, 7-n-amyloxy, 7-i-amyloxy, 7-n-hexyloxy, 7-cyclohexyloxy, 7-n-heptyloxy, 7-n-octyloxy, 7-n-decyloxy, 7-stearyloxy, 7-(2-methoxy)ethoxy, and 7-benzyloxy derivatives of mitomycin A. Most of these compounds displayed antibacterial activities against Gram-positive and Gram-negative bacterial strains and strong inhibition ;of growth of HeLa S-3 cells in vitro.
Co-pending U.S. patent application Ser. No. 647,055 now U.S. Pat. No. 4,888,341 discloses compounds of formula IV with a substantial degree of antitumor activity in animals ##STR10## wherein: Y is hydrogen or lower alkyl; and X is a radical of the formula --O--R, wherein R is: a substituted lower alkyl radical selected from the group consisting of mono- and di-hydroxy lower alkyl, cyano lower alkyl, halo lower alkyl, lower alkyl amino lower alkyl, hydroxy lower alkylthio lower alkyl, hydroxy lower alkyldithio lower alkyl, di-lower alkoxy lower alkyl, hydroxy or lower alkoxy substituted lower alkoxy lower alkyl, and cyclo lower alkyl substituted lower alkyl; or
a lower alkenyl radical; or
a lower alkynyl radical; or
a substituted or unsubstituted oxygen-containing heterocyclic radical selected from the group consisting of tetrahydrofuranyl or lower alkyl substituted derivatives thereof, lower alkyl substituted oxiranyl, lower alkyl substituted dioxolanyl, lower alkyl substituted tetrahydro pyranyl, or lower alkyl substituted furanyl.
Also pertinent to the background of the present invention are the following references: Cosulich, et al., U.S. Pat. No. 3,332,944; Matsui, et al., U.S. Pat. No. 3,410,867; Nakano, et al., U.S. Pat. No. 4,231,936; Matsui, et al., U.S. Pat. No. 3,429,894; Remers, U.S. Pat. No. 4,268,676; Matsui, et al., U.S. Pat. No. 3,450,705; Matsui, et al., U.S. Pat. No. 3,514,452; Imai, et al., Gann, 71: 560-562 (1980); Iyengar, et al., Journal of Medicinal Chemistry, 26(1): 16-20 (1983); Shroeder, et al., U.S. Pat. No. 3,306,821; and Andrejewski, et al., German Patent No. 2 837 383.